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Retraction comes as death of PI leads to lost records

The Journal of Experimental Medicine has retracted a 2011 article after the principal investigator’s home institution suggested that the PI might have manipulated his data. Complicating matters, the PI in this case died two weeks after the paper appeared and his notes have gone missing — making an affirmative declaration of fraud or honest error difficult.

At the request of the Dean for Research, Mayo Clinic Arizona, the paper “Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth” by Zorro-Manrique, et al. is now retracted. The Dean states:

“We have recently received requests from readers to clarify the methodology and results in the paper presented by Zorro Manrique and colleagues. Regrettably, the senior investigator, Dr. Joseph Lustgarten, has passed away, and we do not have reliable access to his full methodology and data to substantiate the paper’s claims. In our ongoing efforts to respond to reader requests, concerns have arisen that individual methods, controls, labels, and data magnitude may be inaccurately portrayed in the paper. Although the surviving authors maintain a strong conviction that the paper’s substance, and the underlying science of regulatory macrophages, are valid, we request the retraction of this manuscript for the reasons stated above.

The reagents provided by co-authors outside of the Mayo Clinic are not implicated in these concerns.

No finding of research misconduct was made concerning the contributions of the surviving authors.”

The study has been cited twice, according to Thomson Scientific’s Web of Knowledge.

The case is broadly reminiscent of one we covered earlier this year involving a researcher at Mount Sinai in New York who died about a month before four of her papers were retracted by the Journal of Biological Chemistry over concerns about misconduct. And there was the case of Julio Cruz, described in the BMJ several years ago (thanks to Charlie Briar for reminding us of it):

Cruz, a previously highly regarded medical researcher and clinician, committed suicide two years ago. Three of his publications about the use of high dose mannitol in head injury have recently been called into question. Furthermore, his coauthors and the editors of the journals in which the three papers were first published have failed to respond adequately to concerns raised about the integrity of the data in these papers.

The dean of research at Mayo Scottsdale is Keith Stewart. We wanted to know why a retraction was necessary, considering that the remaining authors stand by the results — at least, writ large.

Stewart told us that “two or three” labs familiar with Lustgarten’s work raised concerns about the paper shortly after it was published, but Lustgarten died June 30, of gastric cancer, at age 48. Using the records available — precisely what was around seems to be fuzzy — the clinic found inaccuracies in Lustgarten’s work.

There was enough concern in the review of that data to lead us to request a retraction of the paper. It’s hard to be absolutely sure. …

Dominique Hoelzinger, Lustgarten’s Mayo colleague and a co-author of the JEM paper, provided a little more detail:

The people who were writing us were trying to reproduce the isolation of these cells. They found out that certain controls were not executed; when one does execute them, it’s hard to replicate the level of cell [activity reported in the paper.

According to Hoelzinger, however:

We don’t have any of his notes because they were mistakenly disposed of right after he passed away

The last line of the retraction notice certainly implies that Mayo suspected Lustgarten of misconduct, but neither Stewart nor Hoelzinger would go that far. Hoelzinger told us:

It’s so hard to say this sort of thing about a person who cannot stand up and defend himself. This has been a extremely difficult situation. … It has been a very sad time for us.

Hoelzinger and Lustgarten also collaborated on a 2011 article in Cancer Immunology, Immunotherapy, the results of which have not been questioned. Meanwhile, she said, she and her co-authors from the JEM paper continue to work in the area they studied.

This is still a viable project.

Meanwhile, the Mayo investigation is ongoing, as investigators try to figure out if any misconduct involved government funding. Lustgarten had received “three or four” NIH grants, Stewart said, “two or three” of which have been cleared of any wrongdoing.

I love the comment at the end of the article that I’ve linked to: “Competing interests: RS has a longstanding interest in research misconduct and was a founder member of the Committee on Publication Ethics. The only way that he could benefit financially from this article is if more people were to buy his book, which includes a chapter on research misconduct.”

How heartless is it to retract the paper just soon after such a tragedy. Dying of cancer at only 48! I guess he had been battling his cancer for some time before that and may be while preparing the paper. Not an eviable scenario, isn’t it?

They could leave it alone at least in memory of this fellow doctor. Imagine how happy he was to see his paper in JEM while he had only two weeks to live. May be it brightened his last days a little bit.

After all, if he was alive may be he would defend his paper.

This is the first time I am not happy at all reading about a retraction.

Oh, if all the millions of “correct” papers about cancer could lead to any patient not dying from cancer…

Ralph Steinman even got a Nobel Prize for his very correct papers about cancer, but died of cancer at a relatively early age. So sadly, he missed the news just by a few days and died without knowing of his Prize.

Dr. Lustgarten might have had a chance to prove his rightness if he was alive, as I mentioned earlier. We can not deny that possibility for sure. And it is better to be very careful with damaging reputation of people who have no chance to argue and defend themselves. Such name smearing is forever.

On the practical note, it is a very long way from a paper or idea to a drug or treatment that is used in patients. The long sequence of laboratory, pre-clinical and clinical trial stages is aimed at prevention not only from “incorrect” treatment, but in the bulk from a lot of non-efficient drugs.

“if all the millions of “correct” papers about cancer could lead to any patient not dying from cancer”.

The fact is that some did.

The epidemiological work on smoking and lung cancer by Doll and Peto going back to the 1950s springs to mind. This work has led to millions of people not getting lung cancer principally, and not dying from cancer.

Once you get cancer it is more difficult, but even then there are some quite impressive sucesses.
Treatment of leukaemia (a malignancy, it counts as a “cancer”) has improved considerably, spectacularly so in children, and still markedly in adults, in the last 50 years, in fact it has gotten better with each decade.
The solid tumours are more difficult, but with these there has been success.
Sometimes this comes from understanding the biology, more often from clinical trials.
The results of clinical trials, if carried out well, do count as scientific papers.
There will be some variable, and the effect of this variable is measured.

The other issues you mention seem somewhat tangential.

The point is that we do need to find out what is incorrect. Imposing Victorian morality on the issue does not improve transparency.

Maybe an issue is that the authorities should have investigated/come to their conclusion when the person was still alive (the lack of transparency just stores up problems), but that is not a reason to ignore the findings.

Thank you for your comments, David. I can add a few points to that, although I do not want this blog to descend from discussing the topic to discussing someone’s comments and evaluating them. I believe such approach is wrong and contra-productive.

I by no means intended to undermine the great efforts and achievements of cancer researches (since I am one of them as well, to some extent). The scientific achievements have been great in the last decades, no doubt. The clinical acievements gave been big. Whether they have been big enough or not enough – let’s not engage in this discussion here.

Surely, there have been improvements in treatment of cancer, including leukemia, with the recent breakthrough targeted therapies leading to extended survival in certain subsets of patients. We all know the examples both from the peer-reviewed publications and from the media.

However, I think it would be a simplification to say that ”an incorrect paper can lead to people dying from cancer”. So as I am still to see a single paper that could be directly traced to a single cancer patient “not dying from cancer”.

It is interesting for an experimental researcher to have an epidemiological work as the first example coming to mind. This probably proves the point that I made.

People not commencing smoking because of the works of Doll and Peto (probably the influence of those works on The Surgeon General was more important than direct influence of Doll and Peto on people), then not contracting cancer because of not smoking, and then not dying of cancer because of not having cancer – this sequence might, technically, fit into my expression “not dying from cancer”. However I said “patient not dying from cancer” and we can not call “a patient” someone who does not have cancer.

I can have another good example: a surgeon can “cure” some cancers and make patients “not die from cancer”, which does not mean that they live forever, but it means that they die from other, non-related reasons. Then you can link the “correct” paper where he/she describes his/her operations to the patients cured.

A not-so-fit example: the warning of the dangers of smoking on the cigarette pack can cause some people quit or not start smoking, and consequently, not die from cancer. This warning is based on scientific research, but it can not be counted as a scientific paper per se and the tobacco company that printed the pack can not be credited for benefits to cancer patients.

OK, it was a deviation above, and regarding my previous post I apologize if I did not explain some points clear enough, so they could seem “tangible” to some readers.

To clarify it, the meaning of the last paragraph in that post was that between a single “incorrect” (for instance) paper and the patients treated there is a very big “safety” distance. First, it takes not one but very many papers to check and confirm an idea before it becomes a “potential” treatment method or drug. Then, there are a lot of pre-clinical and clinical trial stages to confirm the safety and efficacy. Therefore, as I mentioned above it would be too much a simplification to say that ”an incorrect paper can lead to people dying from cancer”.

With regard to another aspect of this case, I feel that you are sympathetic to potential patients at danger. I think Dr. Joseph Lustgarten also deserves our sympathy. I do not know you, but I myself being just a year shy of 48 can feel the magnitude of the tragedy for a colleague dying at such a young age. And the death of gastric cancer might follow an extended period of treatment and suffering.

Given that Dr. Lustgarten’s other works have been found to be “clear of any wrongdoing”, we must respect him and believe that he spent his short life to the benefit of oncological and other patients.

I should respect the opinion of the Dean for Research at Mayo Clinic Arizona even though based on “two or three”(!!) labs concerns, but I note the fact that the remaining authors stand by the results of the paper.

Back to putting myself into the possibility of such tragedy, I also would not want any actions against my publications to be taken when I am unable to argue. While I am alive I can stand by my publications and my opinions (this is what I am doing). Unfortunately, Dr. Lustgarten does not have the privilege to be able to exchange opinions with you and can not provide his explanations in case if he disagrees with your calling his paper “incorrect”.

My comments were meant to be somewhat general. Most of it was not criticism of your comments.

I take you point about how a single incorrect paper has not led to the death of somebody from cancer (and therefore we shouldn’t blame a single paper and its authors for any deaths. You are quite right.).

“Prevention is better than cure”. In the U.K. the emphasis has been, since at least 1980, on “primary prevention”. Not having patients is a success!

I was talking about the U.K. where the influence of Doll and Peto was quite profound, on the government, and people. Doctors (who read the medical literature) stopped smoking first, then the middle-class..
The effect on the population is the main point.

Epidemiology is science. We are not allowed to do “experiments” with people, so it the “best” that can be done. You might even find that universities set exam questions like: epidemiology has had a greater effect on human health than experiemtal biology. Discuss.

The treatment of nearly all types of leukaemia has gotten better. That is for many reasons, but scientific and medical ones are in there. If you don’t give the patients with acute leukaemia chemotherapy they will nearly all be dead within a month, two at a stetch. That’s why they were called “acute” leukaemias. “Acute” has a specific meaning in medicine and means of short duration. It is not just, or even primarily “the recent breakthrough targeted therapies leading to extended survival in certain subsets of patients”, but before them. Look at the timeline of the statistics below.

When you write “We all know the examples both from the peer-reviewed publications and from the media”, you sound dismissive, as it they were exceptions, recorded, but nevertheless exceptions. I apologize for that criticism, but want to make the point about the numbers, and timeline. One can also look at the graphs from many organisations that show that the survival rates have considerably improved. I write this because it should be true and accurate. The numbers are there.

Thank you for the interesting references. With your permission, I may use that data in my presentations or while talking to patients.

Just to clarify, by saying “we all know the examples” I did not want to say that they are rare, but just that we all know the examples, i.e. there are good examples of the achievements and they are well known.

I think we can conclude at this point in order not to distract the fellow readers of Retraction Watch from making important scientific discoveries by our personal discussion.

I have also attempted to replicate the experiments and found nothing that even resembles the findings in the paper, at a recent conference it also became clear that everyone else seems to have found the same thing, not just two or three labs, keep in mind that if you have access to Foxp3 reporter mice it should be very easy to replicate this data.
I agree that we should avoid smearing the name of the author in question since they are unable to defend themselves but the paper is demonstrably wrong and can’t be allowed to stand.
The idea that the paper should not be withdrawn due to the tragic circumstances of one of the authors is absurd and against every principle of good research.

What with the other co-authors ? Why doesn’t anybody ask S. Gordon why he didnt check the data in more detail? There is very clear guidelines in science, all co-others are responsible for the data… especially senior researchers! This so typical, put a heavy weight name on the paper and it increases the chances to publish in a HI journal…